Infections by intracellular pathogens such as viruses, bacteria and parasites, are cleared in most cases after activation of specific T cellular immune responses that recognize foreign antigens and eliminate infected cells. Vaccines against those infectious organisms have been traditionally developed by administration of whole live attenuated or inactivated microorganisms. Although research has been performed using subunit vaccines, the levels of cellular immunity induced are usually low and not capable of eliciting complete protection against diseases caused by intracellular microbes.
One problem encountered when using live attenuated vaccines is the development of adverse events in some patients. Typical reactions associated with live viral and bacterial vaccines, such as measles, mumps, rubella (MMR) and varicella vaccines, often resemble attenuated forms of the disease against which the vaccine is directed. However, more severe adverse affects have been reported. For example, there is an association between the Urabe strain of mumps vaccine and viral meningitis (Dubey and Banerjee, Indian J. Pediatr. 70:579-84, 2003). In addition, vaccine associated thrombocytopenia has been reported. Although epidemiological studies do not support a causative link between MMR and autism (Chen et al., Psychol. Med. 34:543-53, 2004), the fear remains and likely contributes to poor vaccine acceptance in some regions and sections of society.
In addition, documented safety concerns with vaccines demonstrate the harm that vaccines can cause. For example, the currently available attenuated Sabin oral polio vaccine (OPV) strains are genetically unstable, principally because only 2-5 base substitutions confer the attenuated phenotype (Ren et al. J. Virol. 65:1377-82, 1991). This instability is the underlying cause of vaccine-associated paralytic poliomyelitis in immunologically normal (Strebel et al., Clin. Infect. Dis. 14:568-79, 1992) and in people with B-cell immunodeficiencies (Kew et al., J. Clin. Microbiol. 36:2893-9; Khetsuriani et al., J Infect. Dis 188:1845-52, 2003; Yang et al., J. Virol. 79:12623-34), and of outbreaks associated with circulating vaccine-derived polioviruses (Kew et al., Science 296: 356-9, 2002; Yang et al., J. Virol. 77:8366-77, 2003; Rousset et al., Emerg. Inf. Dis. 9:885-7, 2003; Kew et al., Bull. WHO 82:16-23, 2004; Shimizu et al., J. Virol. 78:13512-21, 2004; Kew et al., Ann. Rev. Microbiol. 59:587-635, 2005). In addition, the CDC recommended suspending use of the rhesus-human rotavirus reassortant-tetravalent vaccine (RRV-TV) due to cases of intussusception (a bowel obstruction in which one segment of bowel becomes enfolded within another segment) among infants who received the vaccine (MMWR Morb Mortal Wkly Rep. 53:786-9, 2004).
Although the primary mode of protective immunity induced by OPV is the production of neutralizing antibody by B-cells, OPV stimulates an immune response similar to that of a natural infection. Immunity against paralytic disease is further enhanced by the production of antibodies in the gastrointestinal tract that limit poliovirus replication, and, thus, person-to-person transmission. The stimulation of intestinal immunity, along with ease of administration, has made OPV the vaccine of choice for global polio eradication (Aylward and Cochi, Bull. WHO 82:40-6, 2004). Therefore, there is a need to identify methods of making an attenuated vaccine that reduces the safety concerns with currently available live attenuated vaccines while retaining the advantages of attenuated vaccines.